Obesity-associated NLRC4 inflammasome activation drives breast cancer progression

Ryan Kolb, Liem Phan, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Ann M. Janowski, Qing Xie, Kathleen R. Markan, Wei Li, Matthew J. Potthoff, Enrique Fuentes-Mattei, Lesley G. Ellies, C. Michael Knudson, Mong-Hong Lee, Sai-Ching J. Yeung, Suzanne L. Cassel, Fayyaz S. Sutterwala and Weizhou Zhang ()
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Ryan Kolb: University of Iowa Carver College of Medicine
Liem Phan: University of Texas Graduate School of Biomedical Sciences at Houston
Nicholas Borcherding: University of Iowa Carver College of Medicine
Yinghong Liu: The Second Xiangya Hospital, Research Institute of Nephrology, Central South University
Fang Yuan: The Second Xiangya Hospital, Research Institute of Nephrology, Central South University
Ann M. Janowski: Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine
Qing Xie: University of Iowa Carver College of Medicine
Kathleen R. Markan: University of Iowa Carver College of Medicine
Wei Li: University of Iowa Carver College of Medicine
Matthew J. Potthoff: University of Iowa Carver College of Medicine
Enrique Fuentes-Mattei: The University of Texas MD Anderson Cancer Center
Lesley G. Ellies: University of California, San Diego
C. Michael Knudson: University of Iowa Carver College of Medicine
Mong-Hong Lee: University of Texas Graduate School of Biomedical Sciences at Houston
Sai-Ching J. Yeung: University of Texas Graduate School of Biomedical Sciences at Houston
Suzanne L. Cassel: Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine
Fayyaz S. Sutterwala: Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine
Weizhou Zhang: University of Iowa Carver College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients.

Date: 2016
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DOI: 10.1038/ncomms13007

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